Since the first documented outbreaks in 1982, infections from enterohemorrhagic Escherichia coli (EHEC), now more commonly referred to as Shiga toxin producing E. coli (STEC), have been a major public health concern in the United States and in Europe. It is recognized that the Shiga and Shiga like toxins of Escherichia coli 0157:H7 and of other Shiga-producing E. coli strains are pathogenesis factors. In the United States, an estimated 73,000 cases of E. coli 0157:H7 and 37,000 non-0157 cases occur annually. Most of the cases occur in children less than 5 years of age. The risk of developing hemolytic uremic syndrome (HUS) following EHEC infection is 3-26%. Usually 5-10% of patients with overt STEC disease develop HUS. There is strong evidence that all postdiarrheal HUS is caused by STEC. Complications of HUS can involve the renal, gastrointestinal, or neurologic systems (Razzaq, Amer. Fam. Physician, 74(6):991-6 (2006)). HUS is recognized as the major cause of kidney failure in infants and children worldwide. About one-third of HUS patients have abnormal kidney function for many years. Approximately 12 of patients with HUS either develop end stage renal disease or die (Garg, et al, JAMA, 290:1360-70 (2003). About 8% have other life long complications such as high blood pressure, seizures, blindness and paralysis (Ostroff, et al., JAMA, 262(3):355-9 (1989); Ostroff, et al., J Infect Dis., 160(6):994-8 (1989)). A small percentage, 0.1-2%, die. Of those who survive HUS, one study showed that half had persistent kidney disease, and 18% progress to end stage renal failure. A study estimating the financial repercussions of E. coli 0157 infections in the United States suggested that annual cost associated with this pathogen is $405 million, with the cost per case varying from $26 for those who do not seek medical care to $6.2 million for a patient with fatal hemolytic uremic syndrome (HUS) (Lockary V M, et al., Emerg Infect Dis [serial on the Internet]. 2007 Aug. http://www.cdc.gov/EID/content/13/8/1262.htm).
As of October 2007, the Center for Disease Control had reported yet another outbreak of E. coli O157, spread by contaminated ground beef. Ill persons reside in 8 states [Connecticut (2), Florida (1), Indiana (1), Maine (1), New Jersey (9), New York (13), Ohio (1), and Pennsylvania (12)]. Thirty-three (89%) of 37 patients with a detailed food history consumed ground beef. Seven illnesses have confirmed associations with recalled products because the strain isolated from the person was also isolated from the meat in their home. Among thirty-three ill persons for whom hospitalization status is known, twenty-one (64%) were hospitalized. Two patients developed a type of kidney failure called hemolytic-uremic syndrome (HUS). No deaths have been reported. The ages of patients range from 1 to 77 years; 50% are between 15 and 24 years old (only 14% of the US population is in this age group).
Even as of 2007, there is no available treatment and antibiotics and anti-diarrheals may exacerbate the problem. Over a quarter century after the discovery of verocytotoxin and the first report by Karmali and colleagues of cases of postdiarrheal hemolytic uremic syndrome (HUS) caused by verotoxigenic Escherichia coli (VTEC), otherwise known as Shiga-toxigenic E. coli (STEC), successful treatment of these infections has remained elusive, reviewed by Goldwater, Expert Rev Anti Infect Ther. 2007 August; 5(4):653-63, and MacConnachie, et al. Curr Opin Infect Dis. 2004 October; 17(5):479-82 Outbreaks of disease have been reported in association with consumption of hamburgers in fast food chains, in nursing homes and in day-care centers. While consumption of contaminated meats, fruits, vegetable and water have led to outbreaks, person to person contact is now recognized as a key mode of transmission (Spika, et al., J Pediatr., 109(2):287-91 (1986)). Although STEC infection occurs mainly in children, adults are also susceptible. Worldwide incidence of STEC infection and HUS appears to be similar to that found in the U.S. Since 1996 STEC infection is notifiable in most states. The disease peaks in the warm months but may occur at any time of the year. Bloody diarrhea usually occurs prior to systemic complications which can be either fatal, due to acute renal failure and serious neurological involvement, or lead to permanent kidney damage. The kidney damage and the neurological symptoms which are caused by one of 2 toxins is known as hemolytic uremic syndrome (HUS). In children there is normally a prodromal period of 4 to 7 days between the bloody diarrhea and development of HUS. During this prodromal period an effective preventative treatment, if one was available, might prevent the development of HUS.
Currently there are three accepted characteristics of all STEC strains. First, they all harbor lysogenic lambdoid phages that encode the Shiga toxins. Prophage induction is likely required for toxin production. Shiga and Shiga-like toxins were previously referred to as verotoxins due to their toxicity to Vero cells. Shiga-like toxins consist of one enzymatically active A subunit and five B subunits that are responsible for cell binding. The toxins are potent protein synthesis inhibitors and are particularly cytotoxic to both HeLa and Vero cells in culture. Based on antigenic relatedness to Shiga toxin, there are two general classes of Shiga-like toxins. Shiga-like toxin I is neutralized by antibody against Shiga toxin, the toxin produced by Shigella dysenteriae type I strains. Shiga-like toxin II is defined as toxin which is not neutralized by antibody directed against Shiga toxin. By amino acid sequence comparison, SLT-I and SLT-II are 56% homologous. The two toxins have identical sets of glycolipid receptors and an identical mode of action. All EHEC strains isolated to date have been found to produce either one toxin or both. The toxins exhibit species specific binding and uptake in the gastrointestinal tract and different strains have different pathogenicity within the same species as well as across species. This has made development of effective treatments extremely difficult due to the general unreliability and lack of predictability of animal models for the human disease.
Therefore, it is an object of the invention to provide 1 human monoclonal antibodies with the ability to neutralize Shiga-like toxin II when the monoclonal antibodies are administered to a human, and thereby treat or prevent toxic uremic syndrome.
It is a further object of the invention to provide human monoclonal antibodies having the ability to neutralize Shiga-like toxin II upon administration to a human, which is dose dependent and has relative few if any adverse side effects.